The intent of the Penn/Wistar SPORE in Skin Cancer is to decrease the morbidity and mortality of skin cancers through the development of targeted therapies. This SPORE investigates three major skin cancers-melanoma, cutaneous T cell lymphoma (CTCL) and squamous cell carcinoma (SCC). The projects and cores focus on the leading cause of skin cancer deaths, melanoma. Our overarching hypothesis is that maximal long-lasting clinical impact achieved by interfering with signaling pathways and/or stimulating the host immune response requires that we take into account tumor-specific and host-specific genetic and epigenetic signatures. Each of the four projects has clear translational objectives and specific hypotheses that rest on a solid body of preliminary studies. The three cores support the projects and the developmental research and career developmental programs. The first overall objective is to develop novel therapies in melanoma. In three bf the four projects, we propose clinical trials of advanced metastatic melanoma with the overall hypothesis that melanoma is not a homogenous disease and, therefore, should be treated with different strategies. Projects 1 and 2 capitalize on our previous findings that two of the major druggable resistance mechanisms to BRAF inhibition in BRAF-mutant melanoma are activation of PI3K signaling and autophagy. Project 1 (Herlyn/Schuchter) proposes extensive tissue-based studies to understand the effects of concurrently targeting mutant BRAF and P13K. We expect the combination to be more effective in killing tumor cells and preventing or extending recurrence in a large subset of patients. Project 2 (Amaravadi/Speicher) combines autophagy and BRAF inhibition in patients with BRAF-mutant melanoma, and identifies other effective targeted therapy and autophagy inhibitor combination strategies that have future development potential for BRAF wild-type patients. Project 4 (Vonderheide/Kalos/June) deals with immunotherapy of melanoma by adoptive transfer of lymphocytes that are engineered to bind to tumor cells. The project is built on highly encouraging data from other malignancies that show activated T cells can achieve effective tumor regression and lasting clinical responses. The second overall objective is to establish new biomarkers in advanced melanoma. We hypothesize that identification of meaningful biomarkers not only will increase our knowledge of the dynamics of disease regression and progression before, during, and after therapy, but also will directly impact the management of the disease by tailored selection of therapy for patients, improved assessment during therapy, and enhanced outcome prediction. In projects 1 and 2, we will analyze patients' melanomas for genetic abnormalities with the intent of stratifying them prior to initiation of therapy into at least five different disease groups that will dictate therapeutic decision-making. We also will determine whether therapy-related changes can be detected in the sera (Project 2), tumors (Projects 1 and 2), and/or blood (Project 4) of patients. Finally, project 3 (Nathanson/Kanetsky) is a genome-wide association study that will investigate inherited genetic susceptibility to acute toxicities and outcomes of immunostimulatory therapy using the anti-CTLA4 drug, Ipilimumab. Here we expect to discover novel genetic signatures that may, after further study, facilitate identification of patient subgroups to help tailor therapeutic decision-making. We expect that this highly interactive SPORE program will yield tangible results for clinical practice in melanoma and other cancers of the skin.